Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

Choy, Ka-Tim; Wong, Alvina Y L; Kaewpreedee, Prathanporn; Sia, Sin Fun; Chen, Dongdong; Hui, K.; Chu, Daniel K W; Chan, Michael Chi Wai; Cheung, Peter Pak-Hang; Huang, Xuhui; Peiris, Malik; Yen, Hui-Ling

doi:10.1016/j.antiviral.2020.104786

Cited by 813 publications

(935 citation statements)

References 33 publications

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“…It is also used to induce vomiting. In addition, it possessed antiviral effects against ZIKV, EBOV, RABV, CMV, HCoV-OC43, HSV-2, EV1, HMPV, RVF, FLUAV, HIV-1 and SARS-CoV-2 (Andersen et al, 2019;Chaves Valadao et al, 2015;Choy et al, 2020;MacGibeny et al, 2018;Mukhopadhyay et al, 2016;Shen et al, 2019;Yang et al, 2018) (https://doi.org/10.1101/2020.03.25.008482). Emetine was proposed to inhibit viral polymerases, though it could have some other targets (Khandelwal et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Homoharringtonine is an anticancer drug which is indicated for treatment of chronic myeloid leukaemia. It also possesses antiviral activities against HBV, MERS-CoV, HSV-1, EV1, VZV and SARS-CoV-2 (Andersen et al, 2019;Cao et al, 2015;Choy et al, 2020;Dong et al, 2018;Kim and Song, 2019;Romero et al, 2007). Homoharringtonine binds to the 80S ribosome and inhibits viral protein synthesis by interfering with chain elongation (Dong et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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Potential antiviral options against SARS-CoV-2 infection

Ianevski

Yao

Fenstad

et al. 2020

Preprint

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As of May 2020, the number of people infected with SARS-CoV-2 continues to skyrocket, with more than 4,5 million cases worldwide. Both the World Health Organization (WHO) and United Nations (UN) has highlighted the need for better control of SARS-CoV-2 infections. Developing novel virus-specific vaccines, monoclonal antibodies and antiviral drugs against SARS-CoV-2 can be time-consuming and costly. Convalescent plasma and safe-in-man broad-spectrum antivirals (BSAAs) are readily available treatment options. Here we developed a neutralization assay using SARS-CoV-2 virus and monkey Vero-E6 cells. We identified most potent sera from recovered patients for treatment of SARS-CoV-2-infected patients. We also screened 136 safe-in-man broad-spectrum antivirals against SARS-CoV-2 infection in Vero-E6 cells and identified antiviral activity of nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine. We found that combinations of virus-directed drug nelfinavir with host-directed drugs, such as salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine exhibit synergistic effect against SARS-CoV-2 in vitro. Finally, we developed a website to disseminate the knowledge on available and emerging treatments of COVID-19.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Potential antiviral options against SARS-CoV-2 infection

Ianevski

Yao

Fenstad

et al. 2020

Preprint

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“…We identified 14 key studies that detailed the antiviral activity of 72 compounds [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Table 1.…”

Section: Identified Papers and Methodsmentioning

confidence: 99%

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Preprint

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There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13 th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of the putative agents tested demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1-and 1.5-fold in lung, respectively. The antiviral activity data reported to date have been acquired under different laboratory conditions across multiple groups, applying variable levels of stringency. However, this analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds which are unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.

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“…2,4,5 In vitro, remdesivir inhibited replication of SARS-CoV-2. 6,7 Moreover, in vitro experiments have shown that mutations conferring resistance to remdesivir do not easily emerge in coronaviruses 8 . Here, we investigated the efficacy of remdesivir treatment in our recently established rhesus macaque model of SARS-CoV-2 infection.…”

Section: Introductionmentioning

confidence: 99%

Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2

Williamson

Feldmann

Schwarz

et al. 2020

Preprint

171

202

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Background: Effective therapeutics to treat COVID-19 are urgently needed. Remdesivir is a nucleotide prodrug with in vitro and in vivo efficacy against coronaviruses. Here, we tested the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection. Methods:To evaluate the effect of remdesivir treatment on SARS-CoV-2 disease outcome, we used the recently established rhesus macaque model of SARS-CoV-2 infection that results in transient lower respiratory tract disease. Two groups of six rhesus macaques were infected with SARS-CoV-2 and treated with intravenous remdesivir or an equal volume of vehicle solution once daily. Clinical, virological and histological parameters were assessed regularly during the study and at necropsy to determine treatment efficacy. Results:In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs. Virus titers in bronchoalveolar lavages were significantly reduced as early as 12hrs after the first treatment was administered. At necropsy on day 7 after inoculation, lung viral loads of remdesivir-treated animals were significantly lower and there was a clear reduction in damage to the lung tissue. Conclusions: Therapeutic remdesivir treatment initiated early during infection has a clear clinical benefitin SARS-CoV-2-infected rhesus macaques. These data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to severe pneumonia.

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Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

Cited by 813 publications

References 33 publications

Potential antiviral options against SARS-CoV-2 infection

Potential antiviral options against SARS-CoV-2 infection

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2

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